Basics of Immuno-Oncology

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Basics of Immuno-Oncology

2016. 6. 25

Kyong Hwa Park MD, PhD

Oncology/Hematology

Korea University Hospital

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Coley’s Toxins

• William Coley (New York surgeon) began intratumoral injections of live or inactivated bacteria (1891)

• Stimulate antibacterial phagocytes that might kill bystander tumour cells

Nature Reviews Cancer 9, 361-371 (May 2009)

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Science 25 March 2011

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Cellular Immunity in Tumor microenvironment

Mast cells

T cells

N1 neutrophils

M1 macrophage NK cells

B cells

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Chronic Inflammation directs Th2 Immunity

Primary tumor-derived factors

Successful metastatic outgrowth

Immune-mediated dormancy/Elimination

Cancer Res October 1, 2013 73; 5852

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CD4+ Treg Immune Regulation

Front. Immunol., 18 November 2013 Targeting DCs

Metabolic disruption

Competition Cytolysis of Teff

Inhibitory cytokines

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Tumor Reprogramed Myeloid Cells

Nature Reviews Immunology 12, 253-268

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Immune Contexture

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Pages et al, NEJM, 2005

Immunity can Impact Disease Outcome:

Role of Th1 CD4 ⁺ T Cells

Galon et al, Science, 2006

Factors Predicting Outcome:

Th1 T

_EM

Central

Dense

>400 samples

75 samples

Th1 Signature: IFN

J Galon et al, Science 2006

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Type, Density, and Location of Immune Cells

J Galon et al, Science 2006

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Association of Immune Cell Infiltration and Prognosis

Fridman WH et al, Nat Rev Cancer 2012

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다음 중 직접 암세포 살상 기능이 알려진 면역세포는?

1) Naïve T cell

2) Dendritic cells

3) Foxp3+ CD4 T cells 4) CD8+ T cells

5) CD19+ B cells

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Cancer Immunity Cycle

Immunity 39, July 25, 2013

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Stimulatory vs Inhibitory Factors in Cancer Immunity Cycle

Immunity 39, July 25, 2013

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How to harness immune system to treat cancer?

- Make TME ‘Inflamed’

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Therapeutic Strategies to Harness

Immune System

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Effect of Anti-cancer Treatment on Immune Cells

Trends in Immunology April 2015, Vol. 36, No. 4, 2015

Indirect Effects Direct Effects

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Malignant Melanoma

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Role of RT in Induction of the Antitumor Immune Response

2013, JCI

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Abscopal Effect by Radiotherapy

N Engl J Med 2012;366:925-31

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M/62, mRCC

• Rt RCC – Radical nephrectomy, clear cell type

• 5년 후 Recur: 1L Bevacizumab/IFNg 임상참여

• 2L Sunitinib: PD

• General condition and organ function - fair

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What’s your next treatment in Korea?

1) Everolimus 2) Pazopanib 3) Axitinib

4) High dose IL-2

5) Nivolumab

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Cytokine therapy: HD IL-2

Clin Cancer Res; 21(3) February 1, 2015

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Durable response & Life Prolongation

Clin Cancer Res; 21(3) February 1, 2015

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Cancer Vaccines

Educating APCs

properly

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GVAX Probably Improves PDA Patients

• GVAX: a human whole cell granulocyte macrophage colony-stimulating factor (GM-CSF) secreting pancreatic cancer vaccine

• Phase II Study in patients received CCRT after R0/R1 resection for PDA

Ann Surg Oncol. 2013 Dec; 20(0 3): S725–S730.

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Combination Strategy: GVAX + PD-1/PD-L1 Ab

J Immunother. 2015 Jan;38(1):1-11

Patients

Mouse

CD8+IFNɣ+ (Spleen, TIL) IFNɣ+ (Spleen, TIL)

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Personalized Immunotherapy based on Tumor Neoantigen

Schreiber et al, JCI Aug 2015

 Neoantigen-specific and self-antigen–specific T cells?

 Proteosomal processing?

 Correct identification of CD4 epitopes?

 In vitro detection of Ag processing and presentation?

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Dendritic Cell in Cancer Immunotherapy

Nature Medicine 6, 966 - 968 (2000)

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DC Therapy for CRPC

Study 1 Study 2

Provenge (n=341) Control (n=171) Provenge (n=82) Control (n=45)

mOS (m) 25.8 21.7 25.9 21.4

HR (95%CI) 0.775 (0.614, 0.979) 0.586 (0.388, 0.884)

p-value 0.032 0.010

www.dendreon.com

US FDA Approval!

April 2010

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Intervention Based on Tumor Burden

 1:10,000 T cells >1:10,000 T cells >1:100 T cells?

Vaccine Prevention

Therapeutic Vaccines

Alternative Strategies

D ise ase Bur d e n

Vaccines Adoptive Cell Therapy

No Disease Microscopic Disease Established Disease

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52세 여자가 우측 발뒤꿈치에 생긴 점을 주소로 내원하여 악성 흑색종 광

범위 절제 및 서혜부 감시 림프절 생검술 및 절제 후 3기암 (BRAF mutant) 으로 진단되었다.

향후 환자의 경과를 호전시키기 위해 적용할 수 있는 가장 적절한 면역학 적 치료법은?

1) Nivolumab

2) CAR-T cell therapy 3) Vemurafenib

4) High dose IL-2 5) Cancer vaccine

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Immune checkpoint Inhibitors

– a new Breakthrough

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Priming phase Effector phase

CTLA-4

PD-L1

NEJM 366;26 2518 June 28, 2012

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History of anti-CTLA Antibody

AACR Cancer Progress Report 2014

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Phase III Trial:

Ipilimumab/gp100 vs Ipilimumab vs gp100

OS Ipilimumab/gp100

(n=403)

Ipilimumab (n=137)

Gp100 (n=136)

mOS (mon) 10.0 10.1 6.4

vs gp100

HR 0.68 (0.55–0.85) 0.66 (0.51–0.87)

P

<0.001 0.003

vs Ipilim

HR 1.04 (0.83–1.30)

P

0.76 ORR 5.7 % 11.0 %

N Engl J Med 363;8 august 19, 2010

US FDA Approval in March 2011

KFDA Approval in Dec 2014

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Mechanisms of PD-1 Expression

Nature Immunology 14, 1212–1218 (2013)

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CD8+T cell Dynamics in Infection

Trends in Immunology April 2015, Vol. 36, No. 4

Acute Ag/functional memory Chronic Ag/ Exhaustion

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PD-1/PD-L1: Exhaustion of T cells

1) Antagonizing TCR signaling 2) Decreased survival,

proliferation, altered metabolism

3) Reduced proliferation via RAS path

4) Altered transcription 5) Altered T cell motility

Trends in Immunology April 2015, Vol. 36, No. 4

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PD-1 and T cell Dysfunction

Jan, 2015, Nature Rev Immunology

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Expression of PD-L 1 in Tumors

Cancer types % PD L-1(+) Cancer types % PD L-1(+)

Melanoma 40-100 Ovarian cancer 33-80

NSCLC 35-95 Gastric carcinoma 42

Nasopharyngeal ca 68-100 Esophageal ca 42

Glioblastoma/

mixed glioma

100 Pancreatic cancer 39

Colon 53 RCC 15-24

HCC 45-93 Breast cancer 31-34

Urothelial cancer 28-100 Lymphomas 17-94*

Multiple myeloma 93 Leukemias 11-42

Chen DS, Clin Cancer Res October 19, 2012.

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Phase I Study of Single-Agent Anti–PD-1 in Refractory Solid Tumors

• MDX-1106 (BMS-936558/ONO-4538)

: fully human IgG4 mAb specific for humanPD-1

• Patients (n=39): CRC(14), Melanoma(10), NSCLC(8), Prostate(6), RCC(1)

Dose (mg/kg) No. of patients

Total No. of Doses Best Response (Duration in month)

1 2 3 5 11

0.3 6 6 0 0 0 0 N/A

1 6 3 1 1 1 0 1 MXR (1)

3 6 3 0 2 1 0 1 CR (21+)

10 21 15 1 4 0 1 2 PR(3+, 16+), 1MXR (1)

Total 39 27 2 7 2 1 1 CR, 2 PR, 2 MXR

Brahmer JR, J Clin Oncol 28:3167-3175. 2010

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Expanded Phase I Study

Dose of anti- PD-1 Ab

Objective

response ORR Duration of

response

Stable disease ≥

24wk PFS rate at

24 wk

Melanoma

NEJM June 28, 2012

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Dose of anti- PD-1 Ab

Objective

response ORR Duration of

response (M)

Stable disease ≥

24wk PFS rate at

24 wk

NSCLC

NEJM June 28, 2012

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NK Cells: Selected clinical trials with expanded allogeneic NK cells

Front. Immunol., 03 June 2015

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Phase I : Random Healthy Donor–Derived Allo-NK Cell Therapy in Patients with Malignant Lymphoma or Advanced Solid Tumors

• Maximum dose (3 × 107 cells/kg, triple infusion): tolerable without significant AE

• Of 17 evaluable patients, 8 patients (47.1%) SD, 9 (52.9%) PD.

Cancer Immunol Res March 2016 4; 215

Treg TGFβ1

MDSC

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Adoptive T cell Therapy

• Genetically engineered TCR expressing T cells

2006 Science

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Genetically engineered T-cell receptor recognizing NY-ESO-1 in Synovial Sarcoma

• T cells transduced with a retrovirus encoding a TCR against an HLA-A*0201 restricted NY-ESO-1 epitope

Clinical Cancer Research, 21 (2015)

Synovial sarcoma (n=18) Melanoma (n=20)

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CAR T-Cell Therapy

: Chimeric Antigen-Receptor based Therapy

Clin Cancer Res; 18(10) May 15, 2012

52

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CAR T-Cell Therapy

: Engineering Patients’ Immune Cells to Treat Their Cancers

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Clin Cancer Res; 18(10) May 15, 2012

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CAR-T cell Therapy in ALL

N Engl J Med 2014; 371:1507-1517

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CAR-T cells Immunotherapy in Solid Cancers

• Target antigen?

• T cell expansion protocol

• Appropriate cell dose

• Patient conditioning

• Monitoring

• Elimination of CART

2016 AAAS, Riddell et al

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Metastatic Cancer Remission

• Patient selection ?

• Anti-tumor immune response?

• How long treat?

• Combination approach?

• Still immune response?

• Retreat?

Clinical Questions that you might have….

PD-1 blockade

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Usual Pattern of Clinical Response

Progressive Disease - 왜 반응이 없는가?

- 항종양 면역 반응의 부재

Stable Disease

- 더 효과를 높일 방법은 없는가?

- Immune signal 증폭 방법은?

Durable responses

- 완전 관해를 이루는 방법은?

- 면역 반응유지를 모니터 할 방법은?

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Rational Application of Immunotherapeutics

• Biomarkers

- PD-1/PD-L1 expression - Mutational load

• Combination strategy

• Immune monitoring

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MPDL3280A (anti-PD-L1) in Urothelial Cell Cancer

Nature, 2014 Nov

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PD-L1 Expression on TILs

Nature, 2014 Nov

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• PD-L1 expression status by IHC: anti–PD-L1 antibody clone 22C3 (Merck)

• Cells counted: neoplastic and intercalated mononuclear inflammatory cells

KEYNOTE-001: Phase Ib study of

Pembrolizumab for the Treatment of NSCLC

N Engl J Med 2015;372:2018-28.

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PFS

All patients

OS

Prev Tx

No Prev Tx

All patients

Prev Tx

No Prev Tx

N Engl J Med 2015;372:2018-28.

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Randomised, phase 3 study of

Nivolumab vs Docetaxel in advanced Squamous NSCLC after one prior Platinum-containing regimen

Stage IIIB or IV squamous-cell NSCLC who had disease

recurrence after one prior platinum-containing regimen

Nivolumab 3 mg/kg q 2 wks

Docetaxel

75mg/㎡ q 3wks

R

1:1

 Stratification: Prior use of paclitaxel therapy (yes vs. no) Geographic region

(United States or Canada vs.Europe vs. rest of the world [Argentina, Australia, Chile, Mexico, and Peru]).

 Primary endpoint: Overall survival

N=272

N Engl J Med 2015;373:123-35.

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N Engl J Med 2015;373:123-35.

9.2 mon vs 6.0 mon

3.5 mon vs 2.8 mon

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N Engl J Med 2015;373:123-35.

• Percent membranous staining in ≥100 tumor cells.

• Archival or recent biopsy

• (Dako North America) used a rabbit monoclonal antihuman PD-L1 antibody (clone 28–8, Epitomics).

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Randomised, phase 3 study of

Nivolumab vs Docetaxel in advanced non-Squamous NSCLC after one prior Platinum-containing regimen

Stage IIIB or IV nonsquamous-cell NSCLC who had progressed during or after platinum-based chemotherapy

Nivolumab 3 mg/kg q 2 wks

Docetaxel

75mg/㎡ q 3wks

R

1:1

• Stratification: Prior maintenance treatment (yes vs. no) Line of therapy (second line vs. third line).

• Primary endpoint: Overall survival N=582

N Engl J Med SEP2015; DOI: 10.1056/NEJMoa1507643

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N Engl J Med SEP2015; DOI: 10.1056/NEJMoa1507643 12.2 mon vs 9.4 mon

2.3 mon vs 4.2 mon

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PD-L1 expression predicts Survival

N Engl J Med SEP2015; DOI: 10.1056/NEJMoa1507643

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PD-L1 as a Biomarker?: Issues

• Tumor heterogeneity

• Interval between biopsy and treatment

• Primary vs metastatic disease

• Ab and staining conditions

• Defining a positive result (cut-offs) - Immune cells vs tumor cells

- Location of expression: intracellular vs surface vs stroma - Intensity, percent of positive cells

- Distribution

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Estimate of the Neoantigen Repertoire in Human Cancer.

Science 3 April 2015

Somatic mutation frequencies (mutation burden) observed in “exomes” from

3,083 tumor–normal pairs.

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PD-1 Blockade in mCRC

N Eng J Med, Jun 2015

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Prognosis

N Eng J Med, Jun 2015

Progression Free Survival for CRC Overall Survival for CRC

How about the efficacy of PD-1 blockade in other cancers with MRD?

Uterus, stomach, biliary tract, pancreas, ovary, prostate, and small intestine

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Mutational Landscape of Melanoma

according to the CTLA-4 blockade Response

Snyder A et al. N Engl J Med 2014;371:2189-2199.

Mutational Load

Survival in Discovery set

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Nonsynonymous mutation burden associated with clinical benefit of anti–PD-1 therapy: NSCLC

Science 3 April 2015

Mutational burden vs Response

Mutational burden vs Prognosis

Smoking vs Prognosis

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Mutation burden, clinical response, and factors contributing to mutation burden: NSCLC

Science 3 April 2015

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Neoantigen burden & Intratumoral Heterogeneity (ITH)

Science MAR 2016

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다음 중 항 PD-1/PD-L1 저해제 치료로 가장 큰 임상적 이득이 가장 적을 것으로 예상되는 환자는?

1) Luminal A type 골전이만 있는 32세 유방암 환자

2) Lynch syndrome으로 진단받은 43세 전이성 대장암 환자 3) 흡연력이 있는 56세 4기 폐편평상피세포암 환자

4) BRCA1 돌연변이가 있는 36세 전이성 삼중음성 유방암 환자

5) 50갑년의 흡연력이 있는 72세 전이성 방광암 환자

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Nanda et al, 2014 SABCS

Monotherapy might not be enough!

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Rational Application of Immunotherapeutics

• Biomarkers

- PD-1/PD-L1 expression - Mutational load

• Combination strategy

• Immune monitoring

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Therapeutic Strategies to Harness Immune System

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Combination of anti-CTLA4/anti-PD-1 in Untreated Melanoma

Postow MA et al. N Engl J Med 2015;372:2006-2017.

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Rational Application of Immunotherapeutics

• Biomarkers

- PD-1/PD-L1 expression - Mutational load

• Combination strategy

• Immune monitoring

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Strategies for Immune Monitoring

Annu. Rev. Med. 2014.65:185-202

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CD8+ T cells with Pembrolizumab

Nature 515, 568–571 (27 November 2014)

Response (n=22)

Progression (n=24)

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Proliferating CD8+ T cells in Regressing Tumors

Nature 515, 568–571 (27 November 2014)

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Anything in blood?

- Immune cell profiles - Cytokines

- PBMC Immunomics

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Baseline serum Cytokine score impacts OS in NSCLC

• Explorative analysis of CM-063 and 017

• SQ-Cytoscore: IL-6, FRTN, CRP, MIP-16, Ip-10, IL-16, MICA, IL-1RA, MMP3, MIG, ICAM1, VDBP, vWF

2016 ASCO

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Personalized Immunotherapy Strategy

Briefings in Bioinformatics, 2015, 1–15

Optimized

Immunotherapy

Protocol Computational

Immunotherapy : Vaccine etc

Immune Monitoring Patient

Profiling

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Future Oncology Treatment Paradigm…

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Biomarkers

supported by - Genomics

- Seromics - Immunomics

Personalized, Combined,

Immunotherapy

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Summary & Future…

• Immunotherapy changed the paradigm of cancer therapy.

• CTLA-4 opened the door to age of immunotherapeutics for cancer.

• PD-1/PD-L1 antibodies harnessed new cancers to immunogenic ones.

• Identification of combinatorial strategy is a future direction.

• Development of predictive biomarkers is ongoing.

• More Understanding about tumor biology.

• Characterizing tumor immune microenvironment according to types and stages of tumors.

• Rational application of ‘omics’ for personalized approach.

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Basics of Immuno-Oncology